The treatment of parkinsonism with 3-(omega-substituted alkyl)-indoles

ABSTRACT

3-(Omega-substituted alkyl) indoles and their use in the treatment of Parkinsonism.

United States Patent [191 Welstead, Jr. 1 June 28, 1974 THE TREATMENT OFPARKINSONISM 424/274, 267

WITH S-(OMEGA-SUBSTITUTED ALKYDJNDOLES [56] References Cited [75]Inventor: William J. Welstead, Jl'., Richmond, UNITED STATES PATENTS3,075,986 1/1963 Jacob 260/294 [73] Assignee: A. H. Robins Company,Inc., 3,183,235 5/1965 Zenitz 260/294 Richmond, Va 3,217,011 11/1965Zenitz 260/294 3,238,215 3/1966 Zenitz 260/294 [22] Filed: Oct. 23, 1965[21] Appl. No.: 504,087 Primary Examiner-Stanley J. Friedman [52] U.S.C1 424/267, 260/294, 260/294.3, [57] ABSTRACT 260/294'7 26052615 424/2743-(Omega-substituted alkyl) indoles and their use in [51] h lt. thetreatment of Parkinsonism. [58] Field of Search 167/65 M, 65, 65 AC; 1

260/294.7 G, 294 A, 294.3 A, 326.15;

7 Claims, N0 Drawings THE TREATMENT OF PARKINSONISM WITH3-(OMEGA-SUBSTIIUTET) ALKYl -IlflDOLES The present invention relates tocertain heterocyclic organic compounds which may be referred to as 3-(omega-substituted alkyl) indoles, acid addition and quaternary ammoniumsalts thereof, therapeutic compositions containing the same as activeingredients, and methods of making and administering them.

The novel compounds of the present invention have utility asphysiologically active agents and are particularly effective indiminishing the tremors and muscular rigidity of Parkinsonism. Thecompounds are also useful as tranquilizers.

Prior art literature contains examples of 3-(omega substituted alkyl)indoles. Those which have been examined in animal bodies have shownlimited therapeutic value and are not disclosed to have anti'Parkinsonactivity. More recently a series of l-,2-, and 3-[2-(4- substitutedpiperazinyl)ethyl]indoles has been the subject of US. Pat. No. 3,188,313with the disclosure of their therapeutic application as CNS depressants.However, these are likewise not disclosed to have anti- Parkinsonismacitivity.

Medicaments that have been used to ameliorate the symptoms ofParkinsonism have been derived from the belladonna group of alkaloids,particularly atropine and scopolamine; in addition synthetic medicinalssuch as Pa'rsidol (TM), Artane (TM), Kemadrin (TM) and Disipal (TM)among others and certain antihistamine compounds have been used withvarying degrees of success. Although all of the aforementioned drugshave been of therapeutic value in treating the tremors and muscularrigidity of Parkinsonism, prior to this invention no single preparationhas been found to be universally tolerated. Moreover, all previouslyknown drugs which have been demonstrated to be useful in treatingParkinsonism have produced undesirable side effects, and in someinstances the effective therapeutic dose produces the toxic symptomscommon to all the drugs, including, for example, dryness of mouth,nausea, giddiness, blurred vision, nervousness, tinnitus, sore mouth,mental confustion, marked agitation, epigastric burning, heavy feelingin the limbs of sensations of tingling in them, disorientation, anorexiaand transient psychotic episodes. The ability to suppress thedistressing and sometimes incapacitating symptoms of Parkinsonismwithout concurrent undesirable side effects is highly desirable in ananti-Parkinson agent. Agents possessing this ability have beendiligently sought.

It is an object of the present invention to provide novel compounds thatare useful in the palliative treatment of Parkinsonism. An additionalobject is the provision of compounds useful as anti-Parkinson agents andwhich produce minimal side effects. A further ob ject is to provide amethod of using said drugs in the treatment of living animal andespecially mammalian bodies. A still further object is to providepharmaceutical compositions which embody the said agents. A stillfurther object is to provide a method for preparing said novel 3-(omegasubstituted alkyl) indoles. Additional objects will be apparent to oneskilled in the art and still further objects will become apparenthereinafter.

The novel compounds of the present invention can be represented by thefollowing formula:

wherein:

R is selected from the group consisting of hydrogen. lower-alkyl,lower-alkanoyl, aroyl, monocarbocyclic aryl, phenyl-lower-alkyl andcycloalkyl; R is selected from the group consisting of hydrogen,lower-alkyl and monocarbocyclic aryl; R" is selected from the groupconsisting of halogen having an atomic weight less than 80,trifluoromethyl, hydroxyl, lower-alkyl, loweralkoxy and aralkoxy; R' isselected from the group consisting of monocarbocyclic aryl and hydrogen;A is selected from the group consisting of hydrogen, loweralkyl,lower-alkynyl, lower alkanoyl, monocarbocyclic aryl, monocarbocyclicaroyl and monocarbocyclic aryl carbamoyl; n is an integer from 0-3inclusive and m is either zero or one.

In the definition of symbols in the foregoing Formula (l) and where theyappear elsewhere throughout this specification, the terms have thefollowing significance.

The term lower-alkyl as used herein includes straight and branched chainradicals of up to five carbon atoms inclusive and is exemplified by suchgroups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, amyland the like. Lower-alkoxy" has the formula --o--lower-alkyl. The termcycloalkyl as used herein includes primarily cyclic alkyl radicalscontaining three up to nine carbon atoms inclusive and encompasses suchgroups as cyclopropyl, cyclobutyl, cyclopentyl, methylcyclohexyl,ethylcyclopentyl and propylcyclohexyl. Included in the term phenylloweralkyl" are groups such as benzyl, phenethyl, methylbenzyl, phenpropyland the like. Lower-allkanoyl has the formula Ill lower-alkyl. Aroyl hasthe formula monocarbocyclic aryl, and aralkoxyl has the formula:o-lower-alkyl-monocarbocyclic aryl.

By monocarbocyclic aryl is meant a phenyl radical or a phenyl radicalsubstituted by one or more substitutents selected from the groupconsisting of halogen having an atomic weight less than 80, lower-alkyl,hydroxy, carboxy, lower-alkoxy and trifluoromethyl. The lower-alkyl andlower-alkoxy radicals can contain up to about three carbon atoms andeach monocarbocyclic aryl radical, together with said substituents, cancontain from six to about nine carbon atoms. When the monocarbocyclicaryl radical is substituted by more than one of the above substituents,the substituent can be the same or different and can occupyany of theavailable positions on the phenyl ring. When the substituent is loweralkyl, said constituent can be straight or branched and can contain fromabout one to about three carbon atoms. Thus when R represents amonocarbocyclic aryl radical it can represent an organic radical such asphenyl or a phenyl radical substituted by one or more substituentssuchas fluoro, chloro, bromo,

methyl, isopropyl, hydroxy, carboxy, methoxy, propoxy ortrifluoromethyl.

This invention also includes acid addition salts of the above definedbases formed with nontoxic organic and inorganic acids. Such salts areeasily prepared by methods known in the art. When the compounds are tobe used as intermediates for preparing other compounds or for any othernon-pharmaceutical use, the toxicity or nontoxicity of the salt isimmaterial when the compounds are to be used as pharmaceuticals, theyare most conveniently used in the form of nontoxic acidaddition orquaternary ammonium salts. Both toxic and nontoxic salts are thereforewithin the purview of the invention. The acids which can be used toprepare the preferred nontoxic acid-addition salts are those whichproduce, when combined with the free bases, salts whose anions arerelatively innocuous to the animal organism in therapeutic doses of thesalts, so that beneficial physiological properties inherent in the freebases are not vitiated by side-effects ascribable to the anions.

The base is reacted with the calculated amount of organic or inorganicacid in aqueous miscible solvent, such as ethanol or isopropanol, withisolation of the salt by concentration and cooling, or the base isreacted with an excess of the acid in aqueous immiscible solvent, suchas ethyl ether or isopropyl ether, with the desired salt separatingdirectly. Exemplary of such organic salts are those with maleic,fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic,propionic, tartaric, citric, lactic, malic, citraconic, itaconic,hexamic, p-aminobenzoic, glutamic, stearic and the like. Exemplary ofsuch inorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids.

In addition, this invention includes pharmaceutically acceptable,nontoxic quaternary ammonium salts of the above defined bases. Thequaternary ammonium salts are readily formed by treatment of thecorresponding free base with the appropriate salt-forming substance,including, for example, methyl chloride, methyl bromide, methyl iodide,methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propylchloride, n-propyl bromide, n-propyl iodide, isobutyl iodide, sec-butylbromide, n-amyl chloride, n-amyl bromide, n-amyl iodide, isoamylchloride, n-hexyl chloride, nhexyl bromide, n-hexyl iodide or similarquaternary salt-forming substances, according to general procedureswhich are well known in the art.

It will be readily apparent to one skilled in the art that certaincompounds of this invention may be present as optical isomers. Theconnotation of the general formulas presented herein is to include allisomers, the separated d or 1 isomers as well as the dl mixtures ofthese isomers.

In general, the novel compounds of this invention are prepared startingfrom readily available selected indoles or from indoles prepared by theFischer indole synthesis. The indoles are reacted with oxalyl chlorideat to 25C. according to the procedure of Speet'er and Anthony, J. Am.Chem. Soc. 76,6208-l0( 1954) in an organic solvent inert under theconditions of the reaction, such as ether, dioxane, and the like to giveindole-3-glyoxyloyl chloride. The preferred solvent is ether.

The indole-3-glyoxyloyl chloride is then reacted with an appropriate4-substituted piperidine or 3-substituted pyrrolidine in a suitablesolvent such as benzene, chloroform, dioxane, toluene, acetonitrile andthe like, which will not enter into the reaction but which will providea rection medium. An acid acceptor which may be an excess amount of thereacting pyrrolidine compound, a tertiary amine or an alkali metal saltof a weak acid may be used, the alkali metal salt of a weak acid, e.g.,sodium carbonate, sodium bicarbonate, potassium carbonate, and the likebeing the preferred acid acceptor. It was observed thatindole-3-glyoxyloyl chloride is not readily hydrolyzed by water at orabout room temperature and in an alternative procedure the reactionbetween an indole-3-glyoxyloyl chloride and the selected substitutedpiperidine or pyrrolidine can be conveniently carried out in achloroform-water mixture. The alternate method is particularlyconvenient when the acid acceptor employed is an alkali metal salt of aweak acid. The-purpose of the acid acceptor is to take up the hydrogenhalide which is split out during the course of the reaction. Thereaction is conveniently carried out at or about room temperature for aperiod of about 3 to 5 hours. Isolation of the product, a l-(indol-3-ylglyoxyloyl)-3-substituted pyrrolidine or 4- substitutedpiperidine, is achieved by dilution of the reaction mixture with water,separation of the organic and aqueous layers, and drying andconcentration of the organic layer. The crude products are best purifiedby crystallization from a suitable solvent, chromatography or formationof a readily crystallizable organic or inorganic salt.

The reduction of the l-(indol-3-ylglyoxyloyl)-3- substitutedpyrrolidines and 4-substituted piperidines to the novel3-[2-(3-substituted pyrrolidinyl)ethyl]indoles and 3-[2-(4-substitutedpiperidinyl)ethyl]indoles of the present invention is achieved by metalhydride reduction in anhydrous tetrahydrofuran. The com pound to bereduced is dissolved or suspended in tetrahydrofuran and added dropwise,under nitrogen, to a stirred suspension of lithium aluminum hydride inthe aforementioned organic solvent. After refluxing the stirred reactionmixture for about 2 to 5 hours, the reaction mixture is worked up byprocedures well known in the art. The indoles may be purified by vacuumdistillation or by crystallization of their well-defined organic orinorganic salts.

The preparation of the novel compounds of the present invention isnotlimited by the preceding described method and they can be prepared byalternative procedures. In one alternative method appropriatelysubstituted indole-3-acetic acids are prepared from appropriatelysubstituted hydrazones by the Fischer indole synthesis. The substitutedindole-3-acetic acids thus prepared are reduced by metal hydrides to thecorresponding substituted 3-(2-hydroxyethyl) indoles. Reaction of thelatter with a thionyl halide furnishes a substituted 3-(2-haloethyl)indole, the gaseous by-products sulfur dioxide and hydrogen halide beingremoved from the reaction system by application of a slight vacuum or bysweeping the by-product gases out of the reaction system by the use ofan inert gas as, for example, nitrogen. By treating the resultingsubstituted 3-( 2-haloethyl) indoles with a selected 3-substitutedpyrrolidine or 4- substituted piperidine in the presence of a suitableacid acceptor which may be an excess of the pyrrolidine compound, atertiary amine or an alkali metal salt of a weak acid, the desired3-[2'(3-substituted pyrrolidinyl) PREPARATION OF INTERMEDIATESPreparation 1 1( lndol-3-ylgloxyloyl )-3-( o-methoxyphenoxy) pyrrolidineTo a stirred mixture of 11.5 g. (0.06 mole) of 3-(0- methoxyphenoxy)pyrrolidine and g. of sodium carbonare in 100 ml. of chloroform and 35ml. of water was added slowly over a 10 minute period 11.5 g. (0.056mole) of indole-3-glyoxyloyl chloride. After stirring one hour ml. ofwater was added and stirring continued an additional 2 hours; Theorganic layer was separated and washed successively with water, 3Nhydrochloric acid, water and 3N sodium hydroxide. The chloroformsolution was dried over magnesium sulfate and concentrated leaving aviscous oil which solidified on standing. The solid was suspended in hotbenzene and treated with absolute ethanol until solution of the solidoccurred. After concentrating the solution to twothirds of the originalvolume, isooctane was added to the hot solution. After cooling 17.0 g.(83 percent) of product separated, m.p. 173 to 176C. Recrystallizationfrom the same solvent system raised the melting point to 175 to 177C.

Analysis: Calculated for C, H N,O,: Found:

Preparation 2 l-[(2-Methylindol-3-yl )glyoxyloyl]-3- hydroxypyrrolidine3-Pyrrolidinol 12.5 g.; 0.144 mole) was added dropwise over a 30 minuteperiod to a vigorously stirred mixture of 32 g. (0.144 mole) of2-methylindole-3- glyoxyloyl chloride, 40 g. of sodium carbonate and 400ml. of dry benzene. After stirring 24 hours at room temperature, 200 ml.of water was added, the original solid suspension changing to a red gum.After standing several days in benzene the red gum solidified to a redsolid melting at 180 to 190. The melting point could not be improved butthin layer chromatography indicated the material to be quite pure. Theuield was 25.0 g. (64 percent).

Preparation 3 b. 3-Pyrrolidinol (0.95 g.; 0.01 mole) was added to astirred mixture of 2.9 g. (0.01 mole) of 5,6?di'methoxy-ind0le-3-glyoxyloyl chloride, 4.0 g. of so dium carbonate andml. of benzene. After stirring overnight at room temperature, 50 ml. ofwater was added. The mixture was stirred 30 minutes, filtered and thecake washed with water and then with benzene. The dried material weighed1.45 g. (45 percent) and melted at 222 to 225.

Preparation 4 Analysis: Calculated for C H N O C.65.l0;H,5.46;N.10.85Found: C.65.19: 11.5.48; N,lO.97

By following the manipulative procedures of Preparations 1-4 andsubstituting for the reactants used therein an appropriatedindole-3-glyoxyloyl chloride and an appropriate 3 -substitutedoxypyrrolidine or 4- substituted oxypiperidine the followingintermediates are prepared.

l (Indol-3-ylglyoxyloyl)-3-(3,4,5trimethoxyphenylcarbamoyloxy)-pyrrolidine l-(Indol-3-ylglyoxyloyl)-3-(4-methoxyphenylcarbamoyloxy)-pyrrolidinel-(Indol-3-ylglyoxyloyl)-3-(3,4,5-

' trimethoxybenzoyloxy)-pyrrolidine trimethoxy-benzoyloxy)-pyrrolidine1-[(2-Phenylindol-3-yl)glyoxyloyll]-3- ethoxypyrrolidine1-[(5-Hydroxyindol-3-yl)glyoxylo yl]-3-(4-methoxyphenyl-carbamoyloxy)-pyrrolidine1-(1ndol-3-y1glyoxyloyl)-3-(2-propynyloxy)- pyrrolidine1-[(5,7-Dichloroindol-3-yl)glyoxyloyl]-3-(omethoxyphenoxy)-pyrrolidine1-[( l -Ethylindol-3-yl)glyoxy1oyl]-3- hydroxypyrrolidinel-[(2,7-Dimethyl-4-chloroindol-3-yl)glyoxyloyl]-3- phenoxy-pyrrolidineTheexamples below illustrate in detail some of the compounds whichcomprise this invention and methods for their production. However, thisinvention is not to be construed as limited thereby in spirit or inscope. It will be apparent to one skilled in the art that numerousmodifications in materials and methods'can be adopted without departingfrom the invention.

Example 1 3-[2-( 3-Hydroxypyrrolidinyl)ethyl]indole A suspension of 11g. (0.043- mole) of 1-(indol-3- ylglyoxyloyl)-3-pyrrolidinol in 50 ml.of tetrahydrofuran was added dropwise, under nitrogen, to a stirredsuspension of 9.8 g. (0.026 mole) of lithium aluminum hydride in 100 ml.of tetrahydrofuran. After addition, the mixture was refluxed for 2hours, cooled, and treated with enough water to destroy the excesslithium aluminum hydride. The resulting aluminum hydroxide was filteredoff and washed thoroughly with tetrahydrofuran. The filtrate wasevaporated on a rotating evaporator to an oil which solidified onstanding. Crystallization from acetonitrile gave a melting point of144-146; yield, 7.7 g. (78 percent).

Analysis:

Calculated for CHHHNZO: c.7301; H.788; N.l2.16

Found: c.7230; H,7.94;N.12.20

. Example 2 2-Methyl-3- {2-[ 3-( 3 ,4,S-trimethoxybenzoyloxy)pyrrolidinyl- ]ethyl}indole To a suspension of 5 g. (0.02 mole of2-methyl-3-[2- (3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole)of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. Themixture was stirred under anhydrous conditions for 24 hours, thentreated with 25ml. of water and stirred an additional hour. Thechloroform layer was separated, dried over magnesium sulfate andevaporated on a rotating evaporator to a viscous oil.

The oil was chromatographed on a Florisil column (60-100 mesh) andeluted with benzene, then benzene with increasing amounts of acetone.Pure product began eluting with 10 percent acetone-benzene; yield 6.2 g.(79 percent). The pure oil slowly crystallized from ethanol giving 4.8g. of crystalline solid melting at 119 to 121.

Analysis: Calculated for C H MO C,68.47; H.690, N639 Found: C, 8.41;H.7.l0; N.6.22

Example 3 with tetrahydrofuran. Evaporation of the combined filtratesgave an oil which would not crystallize. The oil was dissolved inacetone and treated with dry HCl gas. On cooling 18.5 g. of impureproduct precipitated. Recrystallization from isopropanol-acetonitrile(90:10)

gave 13 g. (52 percent) of pure product melting at 208 to 209.

Analysis:

Calculated for C H ClN oz (164.16 H754; N.9.98

Found: (.6437 H.798; N.9.72

Example 4 {2-[3-(3,4,S-Trimethoxybenzoyloxy)pyrrolidinyl ]ethyl}indole YA mixture of 3 g. (0.013 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodiumcarbonate in 40 ml. of chloroform was.

stirred under anhydrous conditions for 24 hours. Then 0.3 g. ofadditional acid chloride was added and the mixture stirred another 24hours. The mixture was treated with 50 ml. of water, stirred for 1 hourand the chloroform layer separated and dried over magnesium sulfate.Evaporation of the chloroform on a rotating evaporator gave an oil whichwould not crystallize.

The product was chromatographed on a Florisil column (60-100 mesh) andeluted with benzene, then benzene with increasing amounts of acetone. At10 percent acetone-benzene pure product began to elute from the column(TLC shows single spot); yield 4.3 g. (78 percent). The glassy solidcould be crystallized from benzene orbenzene-ligroin giving a solidwhich melted between 79 and 86 with gas evolution. Analysis as well asthe infrared spectrum indicated thatthe solid was a benzene solvate.

Analysis: Calculated for JUHJNQOgi C,7l.69', H.682. N.5.57 Found: 1C,71.46; H.677; N.5.94

Benzene mlvule Example 5 1 mesh Florisil, eluting first with benzene andthen benzene with increasing amounts of acetone. At 25 percentacetone-benzene pure product was obtained as a glassy solid; yield 4.2g. (74 percent).

Analysis: Calculated for C,.H N, O,: C.65.58; H.665; N.9.56 Found:C,65.34; 11.6.86; N.9.57

Example 6 '3- 2-[3-(4- Methoxyphenylcarbamoyloxy)-pyrro1id-.

A stirred suspension of 3.5 g. (0.015 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole in 50 ml. of dry benzene was treateddropwise with 2.3 g. (0.015 mole) of p-methoxyphenylisocyanate in 15 ml.of dry benzene. After addition (0.5 hours) the mixture was refluxed for12 hours after which time only a small amount of solid remainedsuspended. The residue was filtered off and the filtrate was evaporatedunder vacuum to an orange gum. The product was dissolved in benzene andchromatographed on 200 g. of 60-100 mesh Florisil, eluting first withbenzene then benzene with increasing amounts of acetone. At 20 percentacetone-benzene pure product wasobtained from the column; yield 3.5 g.(60 percent). The glassy solid would not crystallize.

Analysis:

Calculated for C H N O .C,69.63; 11,6.64; N,l 1.07

Found: C,69.35: H,6.76; N,l l.l2

Example 7 ,6-Dimethoxy-3-[2-( 3-hydroxypyrrolidinyl )ethyl]indolehydrochloride monohydrate A mixture of 5.5 g. (0.017 mole of l-[(5,6-dimethoxy-indol-3-yl)glyoxyloyll-3-pyrrolidinol in 50 ml. of drytetrahydrofuran was added dropwise to a stirred suspension of 2.85 g.(0.075 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuranunder nitrogen. After addition the mixture was refluxed for 4 hours,cooled in ice and treated with a saturated sodium sulfate solution. Theinorganic salts were removed by filtration and washed thoroughly withtetra hydrofuran. The filtrates were evaporated under reduced pressureyielding 4 g. of crude product. Although separation of the pure materialfrom its impurities could be effected using partition chromatography onthin-layer plates, several attempts using larger amounts on a columnfailed.

The remaining crude product (2 g.) was dissolved in isopropanol andtreated with ethereal hydrogen chloride. After standing several days inthe cold the drak gray amorphous solid was filtered off, washed withether and air dried. The product decomposed slowly above 95 and wasshown to be a monohydrate by analysis', yield 0.7 g.

Analysis: Calculated for Found:

Am; ysis: Calculated for C H ClN,O,(dried at 162;): Found: cIsoI Example8 3- 2-[ 3-( o-Methoxyphenoxy)pyrrolidinyl]ethyl} indole hydrochloride Asolution of 13.5 g. (0.037 mole) of I-(indol-3-ylglyoxyloyl)-3-(o-methoxyphenoxy)pyrrolidine in 50 ml. of anhydroustetrahydrofuran was added dropwise to a stirred slurry of 7 g. (0.18mole) of lithium aluminum hydride in 150 ml. of anhydroustetrahydrofuran. The reaction mixture was worked up in the usual mannerand the oily basic material which was isolated was dissolved in etherand treated with ethereal hydrogen chloride. The isolated hydrochlorideweighed 10.7 g.

(73 percent) and melted with decomposition (gas evolution) near 55 as aresult of solvated ether. Thin layer chromatography of a sample ofregenerated free base showed a single spot.

Analysis: Calculated for C H CIN Q: Found (after drying at Examples 919Using the manipulative procedures described in the I above examples thefollowing compounds are pre pared.

Z-Phen'yl-B- 2-( 3 -ethoxypyrrolidinyl )ethyl indole 5-Hydroxy-3--{2-[3-(4-methoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl}indole6-Trifluoromethyl-3-[2-(B-benzoyloxypyrrolidinyl)ethyl]indole3-{2-[3-(2-Propynyloxy)pyrrolidinyl]ethyl}indole5,7-Dichloro-3-[2-(3-omethoxyphenoxypyrrolidinyl)ethyl]indolel-Ethyl-3-[2-( 3-hydroxypyrrolidinyl)ethyl]indole2,7-Dimethyl-4-chloro-3-[2-( 3-phenoxypyrrolidinyl- )ethyl]indole3-[2-(3-Propionyloxypyrrolidinyl)ethyl]indole 5,7-Dihydroxy-3 {2-[3-(4-methoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl}indole3-[2-(4-l-lydroxy-4-phenylpiperidinyl)ethylIindole 3-[ 2-(4-Phenyl-4-propionoxypiperidinyl )ethyl1indole Pharmacology Thecompounds of the present invention were scrrened for anti-Parkinsonsimand were observed to be effective in eliminating the pronounced symptomcomplex of tremor, motor incoordination, lacrimation and catatonia.Injection of 4-methoxyphenethylamine into laboratory animals results inthe syndrome of Parkinsonism. The efficacy of the novel compounds wasdetermined by administering each of them to groups of five mice. Onehour later 4-methoxypheneth'ylamine was given intraperitoneally. Themice were observed for the symptoms of Parkinsonism and a drugseffectiveness was determined by the complete prevention of tremor, motorincoordination, lacrimation and catatonia. The ED of each drug wasdetermined by the injection of appropriate number of doses andsubjecting the results to probit analysis according to the method of J.T. Litchfield and F. Wilcoxon, J. Pharm. and Exptl. Therap. 96, 99(1949).

The high order of activity of the active agents of the presentinvention, as evidenced by tests in lower animals (representative ofwhich are reported herein) is indicative of utility in human beings aswell as in lower animals. It will be clearly understood that thedistribution and marketing of any compound or composition falling withinthe scope of the present invention for use in human beings will ofcourse have to be predicated upon prior approval by governmentalagencies, such as the Federal Food and Drug Administration, which areresponsible for and authorized to pass judgment on such questions.

The invention further provides pharmaceutical compositions comprising,as active ingredient, at least one of the compounds according to theinvention in association with a pharmaceutical carrier or excipient. Thecompounds may be presented in a form suitable for oral or parenteraladministration. Thus, for example, compositions for oral administrationcan be solid or liquid and can take the form of capsules, tablets,coated tablets, suspensions, etc., such compositions comprising carriersor excipients conveniently used in the pharmaceutical art. Thus suitabletableting excipientsinelude lactose, potato and maize starches, talc,gelatin, and stearic and 'silicic acids, magnesium stearate, andpolyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient may be -asterile, parenterally acceptable liquid, e.g., water or a parenterallyacceptable oil, e.g., araehis oil, contained in ampoules.

Advantageously, the compositions may be formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredient. Tablets,coated tablets, capsules, and ampoules are examples of preferred dosageunit forms according to the invention. Each dosage unit adapted for oraladministration can conve-' niently contain 25 to 500 mg., and preferably100 to 250 mg. of the active ingredient; whereas each dosage unitadapted for intramuscular administration can conveniently contain to 150mg, and preferably 50 to 150 mg. of the active ingredient.

Examples of compositions within the preferred ranges given are asfollows:

1. Dissolve 6 and 7 in hot water.

2. This solution, when cool, is mixed with No. 3 and the mixture isstirred until uniform.

3. Dissolve 1,2,4,5 and 8 in this solution and stir until uniform.

Capsules Ingredients Per Cap.

1. Active Ingredient 125.000 mg. 2. Lactose 146.000 mg. 3. Magnesiumstcurutc 4.000 mg.

Procedure 1. Blend 1,2 and 3.

2. Mill this blend and blend again. 3. This milled blend is then filledinto No. 1 hard gelatin capsules.

Tablets Ingredients MgJTab.

1. Active Ingredient 125.0 mg. 2. Corn Starch 20.0 mg. 3. Kelacid 20.0mg. 4. Keltose 20.0 mg. 5. Magnesium Stearate 1.3 mg.

Procedure I. Blend 1,2,3 and 4.

2. Add sufficient water portionwise 'to the blend from step No. l withcareful stirring after each addition. Such additions of water andstirring continue until the mass is of a consistency to permit itsconversion to wet granules.

3. The wet mass is converted to granules by passing it through theoscillating granulator, using 8-mesh screen.

4. The wet granules are then dried in an oven at 5. The dried granulesare then passed through an oscillating granulator, using a IO-meshscreen.

6. Lubricate the dry granules with 0.5 percent magnesium stearate.

7. The lubricated granules are compressed on a suitable tablet press.

Intramuscular Injection Ingredients Per ml.

1. Active Ingredient 50.0 mg. 2. Isotonic Buffer Solution 4.0 q.s. to2.0 ml.

Procedure I. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step No. 1.

3. The sterile solution is now aseptically filled into sterile ampoules.

4. The ampoules are sealed under aseptic conditions.

What is claimed and desired to be secured by US.

Letters Patents is:

l. A therapeutic composition for anti-Parkinsonism comprising (1) aneffective amount of at least about I wherein:

R is selected from the group consisting of hydrogen,

lower-alkyl, lower-alkanoyl, benzoyl, phenyl, phenyllower-alkyl andcycloalkyl having three to nine carbon atoms; 7 i

R is selected from the group consisting of hydrogen,

lower-alkyl and phenyl;

A is selected from the group consisting of hydrogen, lower-alkyl,lower-alkynyl, lower-alkanoyl, phenyl, benzoyl and N-phenyl carbamoyl; I

m is zero or one and n is zero to three inclusive, and

non-toxic pharmaceutically acceptable acidaddition salts thereof.

3. A method of alleviating symptoms of Parkinsonism which comprisesadministering to a living animal body afflicted therewith an effectiveamount of a compound of claim 2.

4. A method of alleviating symptoms of Parkinsonism which comprisesadministering to a living animal body 7. A method of alleviatingsymptoms of Parkinsonism which comprises administering to a livinganimal body afflicted therewith an effective amount of 3-[2-(4- hydroxy-4-phenylpiperidinyl )ethyl lzindole.

2. A method of alleviating symptoms of Parkinsonism which comprisesadministering to a living animal body afflicted therewith an effectiveamount of a compound selected from the group having the structuralformula:
 3. A method of alleviating symptoms of Parkinsonism whichcomprises administering to a living animal body afflicted therewith aneffective amount of a compound of claim
 2. 4. A method of alleviatingsymptoms of Parkinsonism which comprises administering to a livinganimal body afflicted therewith an effective amount of3-(2-(3-hydroxypyrrolidinyl)ethyl)indole.
 5. A method of alleviatingsymptoms of Parkinsonism which comprises administering to a livinganimal body afflicted therewith an effective amount of a hydrohalidesalt of 2-methyl-3-(2-(3-hydroxypyrrolidinyl)ethyl)indole.
 6. A methodof alleviating symptoms of Parkinsonism which comprises administering toa living animal body afflicted therewith an effective amount of2-methyl-3-(2-(3-hydroxypyrrolidinyl)ethyl)indole hydrochloride.
 7. Amethod of alleviating symptoms of Parkinsonism which comprisesadministering to a living animal body afflicted therewith an effectiveamount of 3-(2-(4-hydroxy-4-phenylpiperidinyl)ethyl)indole.